The mitochondrial protein NLRX1 controls the balance between extrinsic and intrinsic apoptosis [Cell Biology]

May 27th, 2014 by Soares, F., Tattoli, I., Rahman, M. A., Robertson, S. J., Belcheva, A., Liu, D., Streutker, C., Winer, S., Winer, D. A., Martin, A., Philpott, D. J., Arnoult, D., Girardin, S. E.

NLRX1 is a mitochondrial Nod-like receptor (NLR) protein whose function remains enigmatic. Here, we observed that NLRX1 expression was glucose-regulated and blunted by SV40 transformation. In transformed but not primary murine embryonic fibroblasts (MEFs), NLRX1 expression mediated resistance to an extrinsic apoptotic signal while confering susceptibility to intrinsic apoptotic signals, such as glycolysis inhibition, increased cytosolic calcium and endoplasmic reticulum stress. In a murine model of colorectal cancer induced by azoxymethane (AOM), NLRX1-/- mice developed fewer tumors than wild type mice. In contrast, in a colitis-associated cancer model combining AOM and dextran sulfate sodium (DSS), NLRX1-/- mice developed a more severe pathology, likely due to the increased sensitivity to DSS colitis. Together, these results identify NLRX1 as a critical mitochondrial protein implicated in the regulation of apoptosis in cancer cells. The unique capacity of NLRX1 to regulate the cellular sensitivity towards intrinsic versus extrinsic apoptotic signals suggest a critical role for this protein in numerous physiological processes and pathological conditions.